Deficiency of nectin-2 leads to cardiac fibrosis and dysfunction under chronic pressure overload

Seimi Satomi-Kobayashi, Tomomi Ueyama, Steffen Mueller, Ryuji Toh, Tomoya Masano, Tsuyoshi Sakoda, Yoshiyuki Rikitake, Jun Miyoshi, Hiroaki Matsubara, Hidemasa Oh, Seinosuke Kawashima, Ken Ichi Hirata, Yoshimi Takai

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca+- independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2-knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2-knockout mice compared with wild-type mice, although both nectin-2-knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2-knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2-knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2-knockout mice. In the hearts of banded nectin-2-knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overload-induced cardiac dysfunction.

Original languageEnglish
Pages (from-to)825-831
Number of pages7
JournalHypertension
Volume54
Issue number4
DOIs
Publication statusPublished - Oct 2009
Externally publishedYes

Fingerprint

Fibrosis
Pressure
Knockout Mice
Adherens Junctions
Myofibrils
Cardiac Myocytes
nectins
Homeostasis
Intercellular Junctions
JNK Mitogen-Activated Protein Kinases
Cell Adhesion Molecules
Dilated Cardiomyopathy
Cardiomegaly
p38 Mitogen-Activated Protein Kinases
Aorta
Immunoglobulins
Protein Isoforms
Phosphorylation

Keywords

  • Cell adhesion molecule
  • Heart failure
  • Intercalated disc
  • Nectin-2
  • Pressure overload

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Satomi-Kobayashi, S., Ueyama, T., Mueller, S., Toh, R., Masano, T., Sakoda, T., ... Takai, Y. (2009). Deficiency of nectin-2 leads to cardiac fibrosis and dysfunction under chronic pressure overload. Hypertension, 54(4), 825-831. https://doi.org/10.1161/HYPERTENSIONAHA.109.130443

Deficiency of nectin-2 leads to cardiac fibrosis and dysfunction under chronic pressure overload. / Satomi-Kobayashi, Seimi; Ueyama, Tomomi; Mueller, Steffen; Toh, Ryuji; Masano, Tomoya; Sakoda, Tsuyoshi; Rikitake, Yoshiyuki; Miyoshi, Jun; Matsubara, Hiroaki; Oh, Hidemasa; Kawashima, Seinosuke; Hirata, Ken Ichi; Takai, Yoshimi.

In: Hypertension, Vol. 54, No. 4, 10.2009, p. 825-831.

Research output: Contribution to journalArticle

Satomi-Kobayashi, S, Ueyama, T, Mueller, S, Toh, R, Masano, T, Sakoda, T, Rikitake, Y, Miyoshi, J, Matsubara, H, Oh, H, Kawashima, S, Hirata, KI & Takai, Y 2009, 'Deficiency of nectin-2 leads to cardiac fibrosis and dysfunction under chronic pressure overload', Hypertension, vol. 54, no. 4, pp. 825-831. https://doi.org/10.1161/HYPERTENSIONAHA.109.130443
Satomi-Kobayashi, Seimi ; Ueyama, Tomomi ; Mueller, Steffen ; Toh, Ryuji ; Masano, Tomoya ; Sakoda, Tsuyoshi ; Rikitake, Yoshiyuki ; Miyoshi, Jun ; Matsubara, Hiroaki ; Oh, Hidemasa ; Kawashima, Seinosuke ; Hirata, Ken Ichi ; Takai, Yoshimi. / Deficiency of nectin-2 leads to cardiac fibrosis and dysfunction under chronic pressure overload. In: Hypertension. 2009 ; Vol. 54, No. 4. pp. 825-831.
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abstract = "The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca+- independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2-knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2-knockout mice compared with wild-type mice, although both nectin-2-knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2-knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2-knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2-knockout mice. In the hearts of banded nectin-2-knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overload-induced cardiac dysfunction.",
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